Clinical Validation of an Immune Quiescence Gene Expression Signature in Kidney Transplantation. Issue 12 (30th December 2021)

• Record Type: Journal Article
• Authors: Akalin, Enver; Weir, Matthew R.; Bunnapradist, Suphamai; Brennan, Daniel C.; Delos Santos, Rowena; Langone, Anthony; Djamali, Arjang; Xu, Hua; Jin, Xia; Dholakia, Sham; Woodward, Robert N.; Bromberg, Jonathan S.
• Is Part Of: Kidney360. Volume 2:Issue 12(2021)
• Page Start: 1998
• Page End: 2009
• Publication Date: 2021-12-30
• Subjects: transplantation -- allograft rejection -- antibody-mediated rejection -- donor-derived cell-free DNA -- gene expression profiling -- kidney transplantation -- T cell-mediated rejection; 616.61
• DOI: 10.34067/KID.0005062021
• Languages: English
• ISSNs: 2641-7650

Abstract

Visual Abstract: Abstract : Key Points: AlloMap Kidney is a gene expression profile developed using candidate genes from the AlloMap assay broadly used in heart transplantation. AlloMap Kidney was validated to differentiate quiescence from rejection in two independent sample sets using a quantitative scale. Blood cell gene expression and donor-derived cell-free DNA contribute independent signals and inform on different aspects of allograft rejection. Background: Despite advances in immune suppression, kidney allograft rejection and other injuries remain a significant clinical concern, particularly with regards to long-term allograft survival. Evaluation of immune activity can provide information about rejection status and help guide interventions to extend allograft life. Here, we describe the validation of a blood gene expression classifier developed to differentiate immune quiescence from both T cell–mediated rejection (TCMR) and antibody-mediated rejection (ABMR). Methods: A five-gene classifier (DCAF12, MARCH8, FLT3, IL1R2, and PDCD1) was developed on 56 peripheral blood samples and validated on two sample sets independent of the training cohort. The primary validation set comprised 98 quiescence samples and 18 rejection samples: seven TCMR, ten ABMR, and one mixed rejection. The second validation set included eight quiescence and 11 rejection samples: seven TCMR, two ABMR, and two mixed rejection. AlloSure donor-derived cell-free DNA (dd-cfDNA) was also evaluated. Results: AlloMap Kidney classifier scores in the primary validation set differed significantly between quiescence (median, 9.49; IQR, 7.68–11.53) and rejection (median, 13.09; IQR, 11.25–15.28), with P <0.001. In the second validation set, the cohorts were statistically different ( P =0.03) and the medians were similar to the primary validation set. The AUC for discriminating rejection from quiescence was 0.786 for the primary validation and 0.800 for the second validation. AlloMap Kidney results were not significantly correlated with AlloSure, although both were elevated in rejection. The ability to discriminate rejection from quiescence was improved when AlloSure and AlloMap Kidney were used together (AUC, 0.894). Conclusion: Validation of AlloMap Kidney demonstrated the ability to differentiate between rejection and immune quiescence using a range of scores. The diagnostic performance suggests that assessment of the mechanisms of immunologic activity is complementary to allograft injury information derived from AlloSure dd-cfDNA. Together, these biomarkers offer a more comprehensive assessment of allograft health and immune quiescence.